| Autor: |
Klamroth R; Comprehensive Care Haemophilia Treatment Center, Vivantes Klinikum im Friedrichshain, Berlin, Germany., Hayes G; BioMarin Pharmaceutical, Inc., Novato, California, USA., Andreeva T; Municipal Center of Hemophilia Therapy, Saint Petersburg, Russia., Gregg K; BioMarin Pharmaceutical, Inc., Novato, California, USA., Suzuki T; Ogikubo Hospital, Tokyo, Japan., Mitha IH; Worthwhile Clinical Trials, Lakeview Hospital, Benoni, South Africa., Hardesty B; Indiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USA., Shima M; Nara Medical University, Kashihara, Japan., Pollock T; ARUP Laboratories, Salt Lake City, Utah, USA., Slev P; ARUP Laboratories, Salt Lake City, Utah, USA., Oldenburg J; Universitätsklinikum Bonn, Bonn, Germany., Ozelo MC; Hemocentro UNICAMP, Department of Internal Medicine, School of Medical Sciences, University of Campinas, Campinas, Brazil., Stieltjes N; Department of Haematology and Regional Centre of Haemophilia Treatment, Hôpital Cochin, Assistance Publique Hôpitaux de Paris (AP-HP), Sorbonne Paris Cité, Université Paris Descartes, Paris, France., Castet SM; Centre de Ressources et de Compétence des Maladies Hémorragiques Constitutionnelles, CHU de Bordeaux, Bordeaux, France., Mahlangu J; Haemophilia Comprehensive Care Centre, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South Africa., Peyvandi F; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy.; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy., Kazmi R; Department of Haematology, Southampton University Hospital, Southampton, United Kingdom., Schved JF; Centre Régional de Traitement des Hémophiles, Hôpital Saint-Eloi, CHRU de Montpellier, Montpellier, France., Leavitt AD; Departments of Medicine and Laboratory Medicine, University of California San Francisco, San Francisco, California, USA., Callaghan M; Division of Pediatric Hematology/Oncology, Central Michigan University, Detroit, Michigan, USA., Pan-Petesch B; Centre Hospitalier Régional Universitaire de Brest, Hôpital A. Morvan, Brest, France., Quon DV; Orthopaedic Hemophilia Treatment Center, Orthopaedic Institute for Children, Los Angeles, California, USA., Andrews J; BioMarin Pharmaceutical, Inc., Novato, California, USA., Trinh A; BioMarin Pharmaceutical, Inc., Novato, California, USA., Li M; BioMarin Pharmaceutical, Inc., Novato, California, USA., Wong WY; BioMarin Pharmaceutical, Inc., Novato, California, USA. |
| Abstrakt: |
Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa ( n = 56), 46.2% in Russia ( n = 91), 40% in Italy ( n = 20), 37.2% in France ( n = 86), 26.8% in the United States ( n = 71), 26.9% in Brazil ( n = 26), 28.1% in Germany ( n = 89), 29.8% in Japan ( n = 84), and 5.9% in the United Kingdom ( n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important. |
